The first clinical report of Acquired Immunodeficiency Syndrome—AIDS (“Sindrome da Imunodeficiencia Humana” in Portuguese) was issued in 1981, After confirming that Human Immunodeficiency Virus (HIV) was the retrovirus that constituted the etiological agent of this disease, many research projects focused seeking a cure for this syndrome. However, no active ingredient has been identified so far that can eradicate the virus from the body.
However, major advances have been achieved in the treatment of AIDS through the development of new antiretroviral compounds. The therapeutic arsenal currently, has 28 medicines, divided into six different classes. Since 1996, treatment has deployed combinations of drugs of different antiretroviral classes in a “cocktail” that has become the standard, commonly known as Highly Active Antiretroviral Therapy (HAART). The introduction of this therapeutic regimen minimized the development of resistant virus
A pioneer, Brazil was one of the first countries to provide free access and distribution to HAART. Medications were channeled to HIV-positive patients through Brazil's Unified National Health System (SUS) under the Medications Policy encompassed by the National Program for Sexually-Transmitted Diseases and AIDS (STD/AIDS), underpinned by Federal Law No 9,313/96. Today, Brazil produces generic antiretroviral medications.
AIDS still remains a global health problem that challenges the scientific community. In 2014, the latest epidemiological bulletin published by the Ministry of Health estimated that 734,000 people were living with HIV/AIDS in Brazil. Access to HAART has significantly increased the survival times of these patients, with fewer deaths. Worldwide, 1, 7 million people died from this disease in 2011, 24% fewer than the peak figure of about 2.3 million cases in 2005.
The etiological agent that transmits this disease is HIV, a retrovirus with two main serotypes: HIV-1 and HIV-2. The most widespread is HIV-1. causing most cases of AIDS. Limited more to West Africa, HIV-2 has lower mutation, virulence and transmissibility rates, replicating more slowly in the human body.
The goal of therapy is to promote the effective reduction of viral replication. The best strategy for achieving this purpose is to use the HAART regimen, as combinations of different drugs inhibit various stages of the replication cycle, significantly decreasing the viral load in the body. Associations may be administered as cocktails (different medications taken simultaneously) or through fixed-dose combined (FDC) Formulations. During the past few years, the use of FDCs has increased, driven by economic advantages for pharmaceutical companies, in parallel to enhanced compliance with treatment, HIV-positive patients.
The drugs approved for AIDS treatment are divided into six classes, by viral replication inhibition point: entry inhibitors (EI); fusion inhibitors (FI); nucleoside reverse transcriptase inhibitors (NRTI); non-nucleoside reverse transcriptase inhibitors (NNRTIs); integrase inhibitors (II) and protease inhibitors (PI).
Tenofovir (TDF) and zidovudine (AZT) are used more for antiretroviral treatment with NRTIs. Among the protease inhibitors (PI), amprenavir (APV) has the longest half-life in the body, in addition to high water solubility and good lipophilicity. However, the use of APV was discontinued in 2003, after the approval of fosamprenavir.
However, despite the existence of this entire therapeutic arsenal, many challenges still remain:                Long duration of the dosing regimen;        Cardiometabolic side effects and other toxic aspects that occur over the long term;        Genetic diversity of the virus and the emergence of drug resistance;        New transmissions from retroviral reservoirs in monkeys;        High transmissivity rate, including strains resistant to available drugs, remaining constant in many parts of the world.        
All these factors have boosted the amount of research in this field, seeking new compounds with known or innovative mechanisms of action. A strategy for obtaining new therapeutic options faster is synthesizing molecules that who structures already contain a unit with recognized antiretroviral activity recognized. With heterocyclic nuclei, isatins and triazoles are considered good prototypes in the quest for substances with potential antiretroviral activity.
According to Morphy R.; Rankovic, Z. (Designed multiple ligands. An emerging drug discovery paradigm. Journal of Medicinal Chemistry, vol. 48, 21, page 6523-6543, 2005) hybrid molecule synthesis been used in order to seek new drugs. Hybrid compounds may be obtained through docking substances with established pharmacological activity and toxicity, and the resulting systems are frequently endowed with enhanced biochemical characteristics, compared to their previous compounds.
There are no references in the literature to compounds derived from Formula 1 isatin used as antiretroviral drugs, with descriptions of only some imine derivatives obtained from this system such as:                Substances obtained from the reaction with lamivudine as prodrugs (SRIRAM, D.; YOGEESWARI, P.; GOPAL, G. Synthesis, anti-HIV and antitubercular activities of lamivudine prodrugs. European Journal of Medicinal Chemistry, v. 40, page 1373 to 1376, 2005);        Compounds obtained from the reaction with sulfonamides as integrase inhibitors (II) (Selvam, P.; Murugesh, N.; Chandramohan, M.; DEBYSER, Z.; Witvrouw, M. Design, Synthesis and anti-HIV activity of novel isatin-sulphonamides. Indian Journal of Pharmaceutical Sciences, vol. 70, 6, pages 779-782, 2008. Selvam, P.; Murugesh, N.; Chandramohan, M.; HOMBROUCK, A.; VERCAMMEN, J.; ENGELBORGHS, Y.; DEBYSER, Z.; WITRROUW M. Inhibition of integrase and HIV replication activity by 4-[{1, 2-dihydro-2-oxo-3H-indol-3-ylidene) amino]-N-(4,6-dimethyl-2-pyrimidinyl)-benzenesulfonamide and derivatives. International Journal of Drug Design and Discovery, Vol. 1, 2, page 161-168, 2010);        Chemical structures synthesized through the reaction with thiosemicarbazide as reverse transcriptase inhibitors (RTI) (Teitz, Y.; BARKO, N.; Abramoff, M.; Ronen, D. Relationships between structure and activity of antiretroviral thiosemicarbazone derivatives. Chemotherapy, v. 40, 3, page 195-200, 1994.        
The literature describes the use of a 3-(cyclopropylethanol)-3-hydroxy-indolin-2-one as RT inhibitors with Formula II replaced by bulky groups at the N−1 position on the indolin)-2-one ring that resulted in the loss of RT activity (BOECHAT, N.; Kover, W B; BONGERTZ, V.; Bastos, M M; ROMEIRO N. C; Azevedo, M L G; Wollinger, W. Design, synthesis and pharmacological evaluation of HIV-1 reverse transcriptase inhibition of new indolin-2-ones. Medicinal Chemistry, Vol. 3, No 6, page 533-542, 2007). In Formula II compounds, it was noted that the insertion of bulky groups at N−1 had no adverse effects on RT inhibitory activity.
There are no reports in the literature on the use of 3,3-difluoro-indolin-2-one derivative Formula III compound as antiretroviral medication, obtained from the reaction with isatin. This presents anti-inflammatory, analgesic, anticonvulsant, anti-Alzheimer, antidepressant, antipsychotic, anxiolytic and anti-Parkinson activities (BOECHAT, N.; Kover, W B; BONGERTZ, V.; Bastos, M M; ROMEIRO N. C; Azevedo, MLG; Wollinger, W. Design, Synthesis and Pharmacological Evaluation of HIV-1 reverse transcriptase inhibition of new indolin-2-ones Medicinal Chemistry, Vol 3, No 6, pages 533-542, 2007; WO 2006008067, 2006; and WO 2015012400, 2015).
This invention comprises the development of multi-target compounds that, in addition to being active, do not present the same problems as seen in drugs currently used to treat the disease. Furthermore, these compounds act as inhibitors of the hepatitis B virus (HBV), which is one of the main co-infections diagnosed in HIV-positive patients.
The hepatitis B virus (HBV) is a chronic infection that affects over 350 million people worldwide remains a threat to global public health (El-Serag, H B Epidemiology of hepatitis and Hepatocellular Viral Carcinoma. Gastroenterology, vol. 142, pages 1264-1273, 2012; Seeger C; Mason, W S; ZOULIM, F.; Hepadnaviruses In: Knipe, D M; HOWLEY, A M (eds) Fields Virology, Philadelphia, Pa.: Lippincott Williams & Wilkins, 2977 pages 2977-3029, 2007). HBV is a member of the hepadnaviridae family (Seeger C; Mason, W S; ZOULIM, F.; Hepadnaviruses In: Knipe, D M; HOWLEY, A M (eds) Fields Virology, Philadelphia, Pa.: Lippincott Williams & Wilkins, pages 2977-3029, 2007). At 3.2-kb, the replication of its viral genome depends on a polymerase encoded by this genome. This viral polymerase is a specialized reverse transcriptase (RT). Thus, similar to HIV RT, HBV TR uses pregenomic RNA (pgRNA) as a template for synthesizing a negative strand of viral DNA (Seeger C; Mason, W S; ZOULIM, F.; Hepadnaviruses In: Knipe, D M.; HOWLEY, A M (eds) Fields Virology, Philadelphia, Pa.: Lippincott Williams & Wilkins, pages 2977-3029, 2007; Hu, J.; Seeger, C. Expression and characterization of hepadnavirus reverse transcriptases Enzymoly Methods, Vol. 275, pages 195-208, 1996). Negative strand DNA synthesis is used for positive-stranded DNA. Hepadnavirus RT consists of four domains. Located in the C-terminal, the catalytic domain presents 78% homology with HIV RT. This consequently justifies the fact that new HIV RT inhibitors also exhibit activity against HBV RT (LANFORD, RE; NOTVALL, G, LEE, H.; BEAMES, B. Transcomplementation of nucleotide priming and reverse transcription between independently expressed TP and RT domains of the hepatitis B virus reverse transcriptase. Journal of Virology, vol 71, 2996-3004, 1997; Seeger C; Mason, W S; ZOULIM, F.; Hepadnaviruses In: Knipe, D M; HOWLEY, P M (.eds) Fields Virology, Philadelphia, Pa.: Lippincott Williams & Wilkins, pages 2977-3029, 2007; Hu, J.; Seeger, C. Expression and characterization of hepadnavirus reverse transcriptases Enzymoly Methods, vol 275, p 195.-208, 1996).